This invention relates to a new chemical process, more particularly to a multistep process whereby a good yield of a pure compound is produced at the final step without the need for separation or purification of intermediate reaction products. The invention relates particularly to the use of a supplementary reaction to eliminate a toxic impurity.
Substituted propionic and butyric acids having the structure ##STR1## wherein R is hydrogen, an alkyl group of 1-7 carbon atoms, or a cycloalkyl group of 5-7 carbon atoms and R' is methyl or ethyl and esters and salts thereof are relatively recently discovered drugs useful for treating inflammation, pain, and fever in man and other animals. Preferred compounds are those where R is a branched alkyl group of 3-7 carbon atoms or a cycloalkyl group. A particularly useful member of this class is 2-(4-isobutylphenyl)propionic acid, also known as ibuprofen, an antiinflammatory drug used for the symptomatic treatment of arthritis and other rheumatic conditions. As compared to earlier known drugs used for the same purpose, for example, aspirin, corticosteroids, and phenylbutazone, ibuprofen has one or more of the advantages of being less irritating and less prone to cause ulcers in the digestive tract on prolonged use, lower toxidity, higher therapeutic ratio, higher solubility in water, and better stability in the presence of moisture. Another member of this class of compounds with similar useful properties is the corresponding butyric acid known as butibufen.
Many processes for the synthesis of these compounds have been described in the art, none of which is comletely satisfactory. Because of their molecular structure, no simple procedure for the synthesis is possible. The synthetic routes described in the literature not only include many separate chemical operations, but also often require expensive or unusual reagents. In addition, these known procedures may involve low yields or undesirably high production of wastes which must be disposed of. Because of the toxicity of certain isomers, homologs, or other possible by-products of a synthesis, some synthetic routes may appear to be impractical because they involve excessive separation and purification procedures for intermediates or for the final product. Representative references describing processes for making ibuprofen and related compounds or intermediates therefor include U.S. Pat. Nos. 3,228,831; 3,385,886; and 3,933,864 and Swiss Pat. Nos. 573,386 and 573,891. The first two U.S. patents in particular (see column 3, lines 40-45 of U.S. Pat. No. 3,228,831) schematically describe a process wherein an alkylbenzene is chloromethylated to make the corresponding alkylbenzyl chloride, the alkylbenzyl chloride is reacted with a cyanide to make the alkylphenylacetonitrile, and the alkylphenylacetonitrile is methylated to produce the 2-(alkylphenyl)propionitrile which is then converted to the carboxylic acid by hydrolysis. However, conventional reaction and separation procedures in such a multistep process where a number of difficulty separable isomers, homologs, and other reaction by-products are inevitably formed would appear to limit that process to low yields and require extensive purification in order to make a final product of the requisite high quality.